Number Of Open Arm Entries Research Articles

The Effects of N-Methyl-d-Aspartate Receptor Blockade During The Early Neurodevelopmental Period on Emotional Behaviors and Cognitive Functions of Adolescent Wistar Rats

The N-Methyl-D-Aspartate (NMDA) receptor is expressed abundantly in the brain and plays an important role in neuronal development, learning and memory, neurodegenerative diseases, and neurogenesis. In this study, we evaluated the effects of NMDA receptor blockade during the early neurodevelopmental period on exploratory locomotion, anxiety-like behaviors and cognitive functions of adolescent Wistar rats. NMDA receptor hypofunction was induced 7-10 days after birth using MK-801 in rats (0.25 mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF), elevated plus maze (EPM) and passive avoidance (PA) tests were used to evaluate exploratory locomotion, anxiety-like behaviors and cognitive functions. In the OF test, MK-801 caused an increase in locomotion behavior (p < 0.01) and in the frequency of rearing (p < 0.05). In the EPM test, MK-801 treatment increased the time spent in the open arms, the number of open arm entries and the amount of head dipping (p < 0.01). MK-801 treatment caused no statistical difference compared to the control group in the PA test (p > 0.05). Chronic NMDA receptor blockade during the critical period of maturation for the glutamatergic brain system (postnatal days 7-10) produces locomotor hyperactivity and decreased anxiety levels, but has no significant main effect on cognitive function during adolescence.

Oral Artesunate-Amodiaquine Combination Causes Anxiolysis and Impaired Cognition in Healthy Swiss Mice.

The present study examined the effects of artesunate –amodiaquine combination therapy on spatial memory and anxietyrelated behaviors in healthy Swiss mice. Neurobehavioural models used were the Y maze and elevated plus maze. Selected for the experiments were eighty adult mice weighing 20-25 g. Forty animals were used in each behavioral model; they were randomly assigned into five groups A, B, C, D and E. Group A served as control and received normal saline, groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunateamodiaquine combination(4 mg/kg and10 mg/kg) respectively while group E animals were given diazepam (5mg/kg). Drugs and vehicle were given orally for three days. The animals were exposed to the elevated plus maze (EPM) and the Y-maze on day 1 immediately after administering the first dose and day 3 immediately after the last dose, the number of entries and percentage time spent in the open and closed arms after five minutes’ exposure to the plus maze and Y–maze spontaneous alternations over a five minute period was scored for each animal. Statistical analysis was carried out using a one way ANOVA followed by a post-hoc test. Results of elevated plus maze tests revealed a significant increase in number of open arm entries and percentage time spent in the open arm and a significant reduction in the total number of arm entries compared to control; Y-maze task performance showed a significant reduction in percentage correct alternations compared to control .In conclusion artesunateamodiaquine administered over a three day period had anxiolytic and memory retarding effects in healthy mice thereby giving an insight into the possible behavioral effects in humans.

Neurological activities of lapachol and its furano derivatives from Kigelia africana

This study was carried out to investigate some neurological activities of lapachol and other chemical constituents isolated from Kigelia africana in male albino mice using elevated plus-maze (EPM) test, open-field test (OFT), and forced swimming test (FST). The anxiolytic-like and antidepressant effects of these constituents were compared to known active anxiolytic (diazepam, 2 mg/kg) and antidepressant (imipramine, 15 mg/kg) reference drugs. The compounds 1 [50 mg/kg, intraperitoneally (i.p.)] and 3 (100 mg/kg, i.p.) significantly increased the number of lines crossed in the OFT and the duration of immobility in the FST, indicating a possible antidepressant activity, but no significant effect was observed in the EPM test. The compound 4 (100 mg/kg, i.p.) significantly increased the time spent on the open arms, but the increase in number of open arms entries was not significant in the EPM test. Meanwhile, the duration of the immobility time was significant and quite close to that of the standard drug, imipramine used in the FST. The compound 5 (100 mg/kg, i.p.) substantially increased the time spent and entries into open arms of the EPM, and reduced the time spent and entries into closed arms, when compared with saline controls (P < 0.05). This compound also increased the exploratory activity of the mice as well as the swimming duration in the OFT and FST, respectively. These results indicate that among the compounds tested, quinones displayed significant anxiolytic and/or antidepressant effects at all doses tested. Kojic acid, a fungal metabolite whose structure was unambiguously confirmed by single-crystal X-ray studies, is also isolated for the first time from K. africana, suggesting that it is a possible taxonomic marker in the biogenesis of the quinone skeleton.

Anxiolytic effects of standardized extract of Centella asiatica (ECa 233) after chronic immobilization stress in mice

Ethnopharmacological relevanceCentella asiatica has long been used for various neurological disturbances in Southeast Asian countries. The present study aims to demonstrate the anxiolytic effect of ECa 233, a standardized extract of C. asiatica containing triterpenoids not less than 80%, in comparison to diazepam. Materials and methodsThe test compound was given orally to non-stressed mice and mice subjected to chronic immobilization stress. Anxiolytic effect was assessed by an elevated plus maze (EPM), a dark-light box and an open-field tests. ResultsAnxiolytic effect of ECa 233 was clearly demonstrated in non-stressed mice subjected to acute stress in all behavioral tests employed. In the EPM test, chronically stressed mice showed significant decrease in the number of open arm entries, shortening the time spent in open arms and an increase of the latency to leave the central area, suggesting their release from the stress. In addition, ameliorating effect of ECa 233 was observed on the body weight and serum corticosterone which were adversely affected by immobilization stress. Madecassoside and asiaticoside, equal to their respective contents of the effective doses of ECa 233, exclusively presented anxiolytic effects in EPM, while no distinct effect was observed on the body weight and serum corticosterone. ConclusionsThe present study demonstrated anxiolytic effect of ECa 233 in both acutely and chronically stressed animals. These effects could be mainly accounted by madecassoside and asiaticoside, suggesting a possible use of ECa 233 for the treatment of both acute and chronic anxiety in the pathological state.

N-Arachidonoyl-serotonin in the basolateral amygdala increases anxiolytic behavior in the elevated plus maze

CB1 receptors in the amygdala have been shown to mediate learned and unlearned anxiety states, however, the role of amygdalar TRPV1 receptors remains unclear. In the present study we investigated the potential anxiolytic action of intra-basolateral amygdala (BLA) infusion of N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and a TRPV1 antagonist. Varying doses of AA-5-HT (0–0.5nmol) were administered into the BLA prior to elevated plus maze testing. AA-5-HT significantly increased both time spent and number of entries into the open arms. Next, to determine whether the anxiolytic effects were the result of blocking FAAH, TRPV1, or whether a combined action was required, rats were given intra-BLA infusions of either 0.25nmol AA-5-HT, 1.0nmol capsazepine (CZP, a TRPV1 antagonist), 0.01μg URB597 (a selective FAAH inhibitor), or vehicle. Again, AA-5-HT increased the time spent in the open arms as well as the number of open arm entries. In contrast, CZP and URB597 did not reliably alter plus maze performance. We then investigated the effects of co-administration of CZP (1.0 or 10.0nmol) and URB597 (0.01 or 0.1μg). At lower doses, co-injections significantly increased both open arm entries as well as the time spent in the open arms, compared to vehicle or either compound alone. While co-administration of the higher doses had no significant effect when compared to either vehicle or CZP treatment, we did observe that open arm activity was elevated in rats receiving combined CZP-URB597 treatment compared to URB597 alone. Overall, our findings indicate that simultaneous FAAH activity and TRPV1 activation are important with respect to the expression of unconditioned fear as mediated within the BLA.

Hyperactivity, increased nicotine consumption and impaired performance in the five-choice serial reaction time task in adolescent rats prenatally exposed to nicotine

Prenatal exposure to nicotine has been linked to accelerated risk for different psychiatric disorders, including conduct disorder, attention deficit hyperactivity disorder (ADHD) and drug abuse. We examine a potential link between prenatal nicotine exposure, hyperactivity, anxiety, nicotine consumption, and cognitive performance in rats. Adolescent offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water and of a group of pair-fed females, used as a control for anorexic effects of nicotine, were evaluated in a battery of tests, including locomotor activity, the elevated plus maze, two-bottle free-choice nicotine solution consumption, the five-choice serial reaction time test (5-CSRTT) and a delay-discounting test. All tests were conducted between postnatal day (PND) 25 and PND 50. Nicotine-exposed animals expressed hyperactivity, increased number of open arms entries in the elevated plus maze and increased numbers of anticipatory responses in the 5-CSRTT. Decreased aversion for nicotine solution in the free-choice test and decreased numbers of omission errors in the 5-CSRTT were observed both in nicotine-exposed and pair-fed offspring. Neither nicotine exposure nor pair-feeding had an effect on impulsive choice in a delay-discounting test. Our study confirms deleterious effects of prenatal nicotine exposure on important aspects of behaviour and inhibitory control in adolescent rats and supports epidemiological findings that show increased levels of symptoms of ADHD and related disorders among those whose mothers smoked during their pregnancy. It also suggests a link between food restriction during pregnancy and addiction-related behaviours in offspring.

Effect of zinc in animal models of anxiety, depression and psychosis

The role of zinc (Zn) in anxiety, depression and psychosis was studied in rodents. Zn was administered at doses of 15 and 20 mg/kg intraperitoneally for 7 days. Both doses of Zn reduced the immobility time and increased the swimming time in the modified forced swim test. In the elevated plus maze test, increases in the number of open arm entries and time spent in the open arms were observed with both doses of Zn. In the amphetamine (1 and 2 mg/kg subcutaneously) induced locomotor activity test both doses of Zn produced reduction in the total movement time, mean velocity and stereotypic movements. Extrapyramidal symptoms such as catalepsy in animals are usually observed with conventional antipsychotic agents; but in the present study, Zn at doses of 15 and 20 mg/kg did not produce any cataleptic state in mice. The results of the present study demonstrated the anxiolytic, antidepressant and antipsychotic-like effects of Zn metal ion, which may be due to its N-methyl d-aspartate receptor antagonistic activity. Concurrent administration of a lower dose of Zn with standard existing anxiolytic and antidepressant drugs in this study showed potentiating effect, suggesting that Zn could exert beneficial role when prescribed as add-on medicine in the psychiatric illnesses. The results obtained in this study are preliminary, as further research is required to confirm the exact role of Zn metal in the investigated central nervous system disorders.

The effect of neonatal N-methyl-d-aspartate receptor blockade on exploratory and anxiety-like behaviors in adult BALB/c and C57BL/6 mice

N-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. In our study, we evaluated the effects of neonatal NMDA receptor blockade on exploratory locomotion and anxiety-like behaviors of adult BALB/c and C57BL/6 mice. In this study, NMDA receptor hypofunction was induced 7–10 days after birth using MK-801 in BALB/c and C57BL/6 mice (0.25mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF) and elevated plus maze (EPM) tests were used to evaluate exploratory locomotion and anxiety-like behaviors. In the OF, BALB/c mice spent less time in the center of the field (p<0.05) and had less vertical locomotor activity (p<0.01) compared to C57BL/6 mice. In BALB/c mice, MK-801 caused a decrease in vertical and horizontal locomotor activity in the OF test, compared to the control group (p<0.05). In C57BL/6 mice, MK-801 treatment increased horizontal locomotor activity and decreased time spent in the center in the OF test (p<0.05). In the EPM, the number of open-arm entries, the percentage of open-arm time (p<0.01) and total arm entries (p<0.05) were lower in BALB/c mice compared to C57BL/6 mice. In BALB/c mice, MK-801 caused an increase in the percentage of open-arm time compared to the control group (p<0.05). In C57BL/6 mice, MK-801 caused a decrease in the percentage of open-arm time compared to the control group (p<0.05).MK-801 decreased exploratory and anxiety-like behaviors in BALB/c mice. In contrast, MK-801 increased exploratory and anxiety-like behaviors in C57BL/6 mice. In conclusion, hereditary factors may play an important role in neonatal NMDA receptor blockade-induced responses.

Anxiolytic action of pterostilbene: involvement of hippocampal ERK phosphorylation

The primary objective of this study was to evaluate the anxiolytic effect of the natural product pterostilbene. Adult male mice administered pterostilbene (1–10 mg/kg, p.o.) were subjected to the elevated plus maze (EPM) test. Pterostilbene manifested anxiolytic activity at 1 and 2 mg/kg doses, demonstrated by increases in % permanence time and number of open arm entries. In addition, the anxiolytic activity of pterostilbene was comparable to that of diazepam in the EPM. The locomotor activity of the animals was unaffected at all doses. Western blot analysis revealed a decrease in both ERK1 and ERK2 phosphorylation in hippocampal homogenates from mice treated with 1 and 2 mg/kg ptserostilbene. Moreover, pterostilbene was detected in the sera and brains of mice following single oral administration. Neither anxiolytic nor motor activity impairment was observed at the higher doses (5 and 10 mg/kg). These results suggest that pterostilbene has the potential to become a candidate compound for therapeutic drug development for anxiety disorders.

Effect of Aripiprazole on Anxiety Associated With Ethanol Physical Dependence and on Ethanol-Induced Place Preference

In the present study, we investigated the effect of aripiprazole, a dopamine system stabilizer, on ethanol-induced psychological and physiological dependence and anxiety-like behavior. First we determined the effect of aripiprazole, a dopamine system stabilizer, on the development and expression of ethanol-induced place preference. Both the development and expression of ethanol-induced place preference was significantly suppressed by treatment of aripiprazole. Next, the withdrawal score gradually increased with increasing duration after the withdrawal from ethanol for 6 days in vehicle-treated mice and the maximal score was observed 10 h after the ethanol withdrawal. Aripiprazole caused no changes in the withdrawal score as compared to vehicle-treated mice. Under these conditions we investigated the effect of aripiprazole on the anxiety-like behavior of ethanol physical dependent mice, which were animals subjected to ethanol vapor for 6 days. The significant decrease of time spent in the open arms and number of open arm entries characterize the anxiety-like behavior in ethanol physical dependent mice, compared to control mice. These decreases were reversed by treatment of aripiprazole, which were inhibited by WAY100635, a serotonin 5-HT1A receptor antagonist. The present findings suggest that aripiprazole was efficient for reversing ethanol-induced place preference and anxiety-like behavior.

Evaluation of Anxiolytic effect of Erythrina mysorensis Gamb. in mice

Aim and Objectives:To evaluate anxiolytic effect of stem bark ethanol and chloroform extracts of Erythrina mysorensis in mice.Materials and Methods:The anxiolytic activity was examined by using the elevated plus maze (EPM) and open field test (OFT), and motor coordination by rotarod test (RRT). Twenty four Swiss albino male mice were divided into four groups of six mice each. Group 1 received vehicle (normal saline); group 2 received diazepam (1 mg/kg); groups 3 and 4 received ethanolic and chloroform extract of Erythrina mysorensis, 200 and 400 mg/kg p.o., respectively.Results:Mice treated with diazepam (1 mg/kg, p.o.) showed significant (P < 0.001) increase ini the percentage of open arms entries and time spent whereas, in closed arm the number of entries and time spent were significantly (P < 0.05) decreased. Oral administration of chloroform and ethanol extract of E. mysorensis exhibited significant (P < 0.05) increase in the number of open arm entries and time spent with significant (P < 0.05) reduction in number of entries and time spent in the closed arm as compared to group 1. Chloroform and ethanol extracts treated mice also produced significant increase in the number of rearings (P < 0.05), assisted rearings and number of squares crossed (P < 0.01). Rotarod test showed significant (P < 0.01) reduction in motor activity at 45 min with diazepam and E. mysorensis extracts (400 mg/kg) as compared to groups 3 and 1.Conclusion:Erythrina mysorensis possess significant anxiolytic activity in the mice. It can be a promising anxiolytic agent.

Pharmacological evidence for the role of nitric oxide in the modulation of stress-induced anxiety by morphine in rats

The present study evaluated the effects of the opioid agonist, morphine on stress induced anxiogenesis and the possible involvement of nitric oxide (NO) in such effects in rats. Acute restraint stress consistently induced an anxiety-like response in the elevated plus maze test, i.e. reduced number of open arm entries and time spent in the open arms as compared to controls. Pretreatment with morphine (1 and 5 mg/kg), attenuated the restraint stress induced anxiogenic response in a dose related manner. Restraint stress induced neurobehavioral suppression was associated with reductions in brain NO oxidation products (NOx) levels, which were also reversed with morphine. Interaction studies showed that sub-effective doses of morphine and l-arginine (a NO precursor) had synergistic effects on stress induced elevated plus maze activity and brain NOx, whereas, l-NAME (a NO synthase inhibitor) neutralized these effects of morphine. Repeated restraint stress (× 5) induced adaptative changes as evidenced by normalization of behavioral suppression and elevations in brain NOx, as compared to acute stress. Pretreatment with morphine in combination with repeated stress (× 5) showed potentiating effects in the induction of behavioral adaptation in the elevatedplus maze and elevations in brain NOx, as compared to repeated stress alone. Further, l-NAME, when administered prior to morphine, blocked this effect of morphine on stress adaptation. These results suggest differential morphine–NO interactions during acute and repeated restraint stress.

Isolation and anxiolytic activity of 3,4-bis(3,4-dimethoxyphenyl)furan-2,5-dione from the ethanolic extract of heart wood of Cedrus deodara

Cedrus deodara heart wood has been traditionally used for the treatment of anxiety. The objective of the study was to isolate the compound from the ethanolic extract and to investigate the anxiolytic activity. The isolated compound was characterized by FTIR, 1H NMR, 13C NMR, and mass spectral technique. The spectral data revealed the structure 3,4-bis(3,4-dimethoxyphenyl) furan-2,5-dione (BDFD). Anxiolytic activity of BDFD was evaluated using elevated plus maze (EPM), Open- field test (OFT) and light–dark model (LDM) in mice. Control mice were orally treated with an equal volume of vehicle (4% gum acacia), and positive control mice were treated with diazepam. In EPM, diazepam and BDFD treated (100 mg/kg) mice exhibited a significant increase in the number of open arm entries and time spent in the open arms (P < 0.001). In OFT, like diazepam BDFD treated mice (100 mg/kg) increased the ambulation (P < 0.001). In LDM, BDFD treated mice (30 and 100 mg/kg) also showed a significant (P < 0.001) increase in the time spent in light arena. In conclusion, the anxiolytic activity of BDFD upon the anxiety models showed a promising result and could be useful for primary medical care.

Effect of ketamine on exploratory behaviour in BALB/C and C57BL/6 mice

In this study, we evaluated the effect of ketamine on exploratory locomotion behaviours in the Balb/c and C57BL/6 strains of mice, which differ in their locomotion behaviours.Intraperitoneal administration of ketamine at three different doses (1, 5 or 10mg/kg, 0.1ml/10 gr body weight) was performed on adult male Balb/c and C57BL/6 mice. The same volume of saline was applied to the control group. The open-field and elevated plus maze apparatus were used to evaluate exploratory locomotion.In the open-field test, Balb/c mice less spend time in the centre of the field and was decreased locomotor activity compared to C57BL/6 mice (p<0.01). Ketamine treatment of Balb/c mice at 10mg/kg dose caused an increase in locomotor activity and an increase in the amount of time spent in the centre in the open-field test, compared to the control group (p<0.05). In C57BL/6 mice, ketamine treatment (1 and 10mg/kg) decreased locomotor activity (p<0.05). In C57BL/6 mice, the three different doses of ketamine application each caused a decrease in the frequency of centre crossing (p<0.001) and the spent time in the centre (p<0.05).In the elevated plus maze, the number of open-arm entries, the percentage of open-arm time and total arm entries were decreased in Balb/c mice compared to C57BL/6 mice (p<0.001). Ketamine treatment of Balb/c mice at 10mg/kg dose caused an increase in the open-arm activity (p<0.001). Ketamine application (10mg/kg) decreased the open-arm activity in C57BL/6 mice (p<0.05).A subanaesthetic dose of ketamine increased exploratory locomotion in Balb/c mice. In contrast, a subanaesthetic dose of ketamine decreased exploratory locomotion in C57BL/6 mice. In conclusion, hereditary factors may play an important role in ketamine-induced responses.

Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB1 receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB1. Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day×6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

Sex-specific influence of exposure to bisphenol-A between adolescence and young adulthood on mouse behaviors

Bisphenol-A (BPA) is one of the most common environmental endocrine disrupters and has a wide range of effects on central nervous system. Adolescence is another important developmental period besides the early critical prenatal and neonatal periods. In the present study, we exposed mice to BPA (40, 400 μg/kg/d) between adolescence and young adulthood for 8 weeks and investigated its effects on the non-reproductive behaviors. In open field tests, rearing and grooming sex differences were abolished by BPA exposure. In the elevated plus maze test, the number of open arm entries, the time spent in open arms, and the number of unprotected head dips in the center area were reduced in males but increased in females by BPA at 40 or 400 μg/kg/d, thus eliminating or reversing sex differences in these behaviors. In the Morris water maze task, exposure to BPA at 40 μg/kg/d significantly extended the average escape pathlength to the hidden platform in males, but no significant influence was found in females; thus, the sex differences in spatial learning and memory were abolished. In the step-down test, the latency to step down from the platform 24 h after receiving a footshock was shortened by BPA exposure in males but not in females; thus, a sex difference was induced in passive avoidance memory in mice. These results suggest that long-term exposure to low levels of BPA between adolescence and young adulthood alters characteristic differences in certain non-reproductive behaviors of males and females, including exploration, anxiety, spatial learning and memory, and passive avoidance memory, although no obvious changes were found in the serum hormone levels or in the weights of reproductive organs.

Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice

Anxiolytic and anxiogenic-like behavioral outcomes have been reported for methylenedioxymethamphetamine (MDMA or ecstasy) in rodents. In the present experiment, we attempted to identify behavioral, hormonal and neurochemical outcomes of MDMA treatment to clarify its effects on anxiety-related responses in 2-month-old Balb/c male mice (25-35 g; N = 7-10 mice/group). The behavioral tests used were open field, elevated plus maze, hole board, and defensive behavior against predator odor. Moreover, we also determined striatal dopamine and dopamine turnover, and serum corticosterone levels. MDMA was injected ip at 0.2, 1.0, 5.0, 8.0, 10, or 20 mg/kg. MDMA at 10 mg/kg induced the following significant (P < 0.05) effects: a) a dose-dependent increase in the distance traveled and in the time spent moving in the open field; b) decreased exploratory activity in the hole board as measured by number of head dips and time spent in head dipping; c) increased number of open arm entries and increased time spent in open arm exploration in the elevated plus maze; d) increased time spent away from an aversive stimulus and decreased number of risk assessments in an aversive odor chamber; e) increased serum corticosterone levels, and f) increased striatal dopamine level and turnover. Taken together, these data suggest an anxiogenic-like effect of acute MDMA treatment, despite the fact that behavioral anxiety expression was impaired in some of the behavioral tests used as a consequence of the motor stimulating effects of MDMA.

Anxiolytic-Like Effects of 4-O-Methylhonokiol Isolated from Magnolia officinalis Through Enhancement of GABAergic Transmission and Chloride Influx

Abstract This study investigated the anxiolytic-like effects of 4-O-methylhonokiol, a neolignan compound of Magnolia officinalis, by using the experimental paradigms of anxiety and compared the results with those of a known anxiolytic, diazepam. A single treatment with 4-O-methylhonokiol (0.1, 0.2, and 0.5 mg/kg, p.o.) or treatment for 7 days (0.5 mg/kg in drinking water) increased the percentage of time spent in the open arms and the number of open arms entries in the elevated plus-maze test. However, the 4-O-methylhonokiol-increased percentage of time spent in the open arm was abolished by treatment with flumazenil, a benzodiazepine receptor antagonist (10 mg/kg). 4-O-Methylhonokiol also increased the number of head dips in the hole-board test, but decreased locomotor activity. Molecular experiments revealed that the α1-subunit of γ-aminobutyric acid (GABA) type A receptors was overexpressed in the cortex of brains of mice after treatment with 4-O-methylhonokiol for 7 days. In addition, 4-O-methylhonokiol also increased chloride influx in cultured cortical cells. It is concluded that 4-O-methylhonokiol may have anxiolytic-like effects and that these effects may be mediated by GABAergic transmission with the increase of Cl(-) channel opening.

Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice

Anxiolytic and anxiogenic-like behavioral outcomes have been reported for methylenedioxymethamphetamine (MDMA or ecstasy) in rodents. In the present experiment, we attempted to identify behavioral, hormonal and neurochemical outcomes of MDMA treatment to clarify its effects on anxiety-related responses in 2-month-old Balb/c male mice (25-35 g; N = 7-10 mice/group). The behavioral tests used were open field, elevated plus maze, hole board, and defensive behavior against predator odor. Moreover, we also determined striatal dopamine and dopamine turnover, and serum corticosterone levels. MDMA was injected ip at 0.2, 1.0, 5.0, 8.0, 10, or 20 mg/kg. MDMA at 10 mg/kg induced the following significant (P < 0.05) effects: a) a dose-dependent increase in the distance traveled and in the time spent moving in the open field; b) decreased exploratory activity in the hole board as measured by number of head dips and time spent in head dipping; c) increased number of open arm entries and increased time spent in open arm exploration in the elevated plus maze; d) increased time spent away from an aversive stimulus and decreased number of risk assessments in an aversive odor chamber; e) increased serum corticosterone levels, and f) increased striatal dopamine level and turnover. Taken together, these data suggest an anxiogenic-like effect of acute MDMA treatment, despite the fact that behavioral anxiety expression was impaired in some of the behavioral tests used as a consequence of the motor stimulating effects of MDMA.

Long-lasting effects of inescapable-predator stress on brain tryptophan metabolism and the behavior of juvenile mice

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase, is the main tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. We investigated the influence of inescapable-predator (rat) stress on behavior and brain TRP metabolism in mice. Male ICR mice (4W) were exposed to 20-min inescapable-predator stress. Behavior on an elevated plus-maze, and TRP, KYN, and 5-HT levels in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei were measured 1 and 4 weeks after stress exposure. Predator stress increased the number of open-arm entries (NOA) 4 weeks after stress exposure without altering the number of closed-arm entries (NCA). Thus, the open/closed-arm entry ratio (NOA/NCA) increased after stress exposure. Predator stress increased KYN levels in the prefrontal cortex (until 4 weeks after stress exposure) and dorsal raphe nuclei (for 1 week after stress exposure), decreased 5-HT levels in all brain regions (until 4 weeks after stress exposure). Thus, predator stress increased the KYN/5-HT ratio in all regions, in particular in the prefrontal cortex and hippocampus until 4 weeks after stress exposure. Predator stress shifted the balance between the KYN and 5-HT pathways to the KYN pathway, and induced behavioral disinhibition.